The Safety and Effectiveness of Surgery
With or Without Raloxifene for the
Treatment of Pelvic Pain Caused by
Endometriosis
Protocol Title
The Safety and Effectiveness of Surgery With or Without Raloxifene for the
Treatment of Pelvic Pain Caused by Endometriosis
Protocol
Identification
Number
99-CH-0012
Phase
2
Multicenter
Yes
Indication
endometriosis
Target Study
Population
Women aged 18 to 45 with endometriosis.
Trial Purpose
Summary
Many women with lower abdominal pain have endometriosis. Endometriosis
is a condition in which the lining of the uterus (endometrium) is found outside
of the uterus. The diagnosis of endometriosis is usually made at surgery. The
treatment of endometriosis includes medical and surgical approaches alone
or in combination. The hormone estrogen stimulates the growth of the
endometrium and may also stimulate the growth of endometriosis. Medical
therapies that act to decrease the level of estrogen can reduce the amount of
endometriosis and pain. When therapies are discontinued, symptoms often
return. In addition, medical treatment for endometriosis is expensive and is
often associated with weak bones (osteoporosis) and hot flashes as a result of
low levels of estrogen.
Surgical treatment is removal or destruction of the endometriosis tissue.
Studies show the pain from endometriosis is relieved longer with tissue
removal than with destruction.
This study was developed to see if surgery followed by daily doses of
Raloxifene (Evista) is effective in reducing pain, for a longer time than surgery
in combination with a placebo (inactive "sugar pill") treatment. Raloxifene
acts like estrogens in some tissues and not like estrogens in others.
Postmenopausal women receiving Raloxifene for the prevention of
osteoporosis had an increase in bone density and an improvement of their
blood lipids (fat content in the blood). However, unlike estrogen, Raloxifene
does not promote the growth of breast tissue or the uterus. If Raloxifene
blocks estrogen action in the lining of the uterus (endometrium) of
reproductive age women, as it does in post-menopausal women, it may also
limit the growth of endometriosis and prevent the return of pain.
Primary Objective
To evaluate the safety and effectiveness of surgical excision of endometriosis
in combination with six months of raloxifene (Evista (TM)) compared with
surgical excision of endometriosis in combination with placebo, to treat
endometriosis-related pelvic pain. Effectiveness will be evaluated as the time
interval to the recurrence of pain and the severity of pain.
Other Objectives
1.To compare the diagnostic utility of fat-suppressed MRI with laparoscopy
for the detection of deeply infiltrating endometriotic lesions.
2. To assess whether the extent, morphologic appearance or depth of
endometriosis as recorded using the ASRM classification system for
endometriosis associated with pain at both the beginning and end of the
study, is correlated with endometriosis-related pain as measured by
questionnaire.
3. To assess whether tissue, blood and urine markers of angiogenesis and
other growth factors are predictive of disease in women with endometriosisrelated pain. Specifically, do the levels correlate with the presence or absence
of disease at laparoscopy and pain scores during treatment?
4. To assess any effects of raloxifene (Evista(TM)) treatment on the menstrual
cycle, quality of life and sexual function, bone density, adrenal function, and
serum lipids.
Primary Endpoint
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Primary Endpoint
Type
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Other Endpoints
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Description of Study
Design
This is a randomized, double-blind, placebo-controlled study of women of
reproductive age who have endometriosis-related pelvic pain. All women will
have had laparoscopically diagnosed and surgically excised endometriosis.
Women will then be randomized to receive raloxifene (Evista(TM)) or placebo
for six months and will be followed for another l8 months to assess
recurrence of persistent pain. All women will have a second laparoscopy to
look for signs of endometriosis either when they have a return of pain or,
after two years of follow-up, for those who remain pain-free. AII women will
be protected from pregnancy by barrier contraception,abstinence or surgical
sterilization for the duration of the study.
Description of
Interventions
A Screening
A1 Medical evaluation (medical history, physical examination, laboratory
testing, questionnaire, symptoms calendar)
A2 Preoperative evaluation (MRI, blood and urine sample and laboratory
testing, home recording of symptoms and pain, menstrual calendar)
A3 Operative evaluation and surgical excision of implants (pregnancy test,
laparoscopic surgery, biopsy and inspection of excised lesions)
B Medical Treatment
C Monitoring
D Recurrence of pain
E Adverse events evaluation
F Study completion evaluation
Inclusion Criteria

Women between the ages of 18 and 45 years, who have their
reproductive organs.

Excellent health other than a three month history of pelvic pain and
documented endometriosis at laparoscopy. Chronic medications may
be acceptable at the discretion of the internist associate investigator
(LN). Use of antidepressants, medications for migraines and
headaches, allergy medications, and treatment of bowel symptoms
such as irritable bowel disease will be allowed.

Do not desire pregnancy for the duration of the study.

Are using abstinence, mechanical (condoms, diaphragms) or
sterilization methods of contraception and are willing to continue
using them throughout the study.

Willing and able to give informed consent.

Willing and able to comply with study requirements.

Less than grade III overweight or BMI less than 40 kg/m(2).
Exclusion Criteria

Women with other causes of chronic pelvic pain including infectious,
gastrointestinal, musculoskeletal, neurologic or psychiatric.

Significant abnormalities in the physical or laboratory examination
including renal and liver function more than twice the normal range.

Hysterectomy or bilateral salpingo-oophorectomy.

Pregnancy.

Lactation.

Use of hormonal contraception, selective estrogen receptor
modulators, progestins, estrogens, steroids, or ovulation induction in
the last 3 months.

Other medical or surgical treatment for endometriosis in the last 6
months.

Untreated abnormal pap smear or other gynecologic condition.

History of venous thrombosis events including deep vein thrombosis,
pulmonary embolism, and retinal vein thrombosis.

Allergy to study drug.

History of stroke, complicated migraine, or documented transient
ischemic attack.

Manic depressive illness or untreated major depression.
Statistical Method
Description
Of the women who complete screening questionnaires for this protocol, we
expect that only 50% will have endometriosis. Thus, we anticipate that 350
women will be screened to accrue 162 who are candidates for laparoscopy.
We estimate that it will take one year to recruit the entire cohort. It is
estimated that 90% of those presenting for laparoscopy will have
endometriosis. Based on the clinical experience of the investigators, about
l0o% of women who begin the clinical study after surgical treatment of
endometriosis may drop out. About l0% of those with excision will have a
return of symptoms by 12 months and 50Yo within two years. A fifty percent
reduction in the recurrence of pain is anticipated with the use of raloxifene. A
sample size of 63 women per group will be required to evaluate this effect
with 80% power using 2-tail test of significance at p : 0.05. Therefore of 156
women who have laparoscopy, 140 will be expected to have endometriosis at
laparoscopy and will be enrolled in the study. Of those, 126 women will
complete the study.
Interval analyses will be done at 6, 12,18 and 24 months, and will be
conducted by Dr.Lee and Dr. Nieman. Assuming it will take one year to accrue
the entire study cohort, the interval analyses at 6 months will review study
progress, patient recruitment, and side effects but not the study endpoint.
Interval analyses at T2, 18 and 24 months will assess the time to recurrence of
pain and pain severity in addition to patient recruitment and side effects. Lan
and DeMets boundaries methods will be used for the interval data analysis. P
value spending function will be used to accommodate the uncertainty of the
progression of the study.If any serious adverse events are noted, study
subject(s) will be unblinded and assessment of drug safety will be made. If
adverse events such as death or deep venous thrombosis, attributable to
study treatment occur, the study be stopped (class 4 common toxicity criteria
occurring with investigational agents using NCI classification system).
To evaluate the efficacy of treatment, the time to recurrence of pain will be
analyzed using the logrank test which also accounts for those patients who do
not experience the recurrent pain (36). The severity of pain will be graded by
an ordinal score and analyzed. For example, the score zero will be assigned to
the pain-free patients and the more severe the pain the higher score will be
assigned. Statistical methods for ordinal score data will be applied to the
analysis of the severity of pain data. If an interim analysis shows a statistically
significant difference between the treatment groups, then the study may be
terminated early.
Statement of the
Proposed Statistical
Model(s)
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Number of Subjects
140
Description of
Interim Analyses
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Subject Minimum
Age
18
Subject Maximum
Age
45
Study uses Healthy
Subjects?
No
Subject Participation
Duration
24 Months
Randomized Study?
Yes
Subject Gender
Female
Blinding
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Control
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Sponsor
Eunice Kennedy Shriver National Institute of Child Health and Human
Development (NICHD)
Study Configuration
Interventional
Planned Countries
USA
Schedule of Activities (optional):
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